sirolimus and Laryngeal-Neoplasms

Topics: Carcinoma, Squamous Cell; Chemoradiotherapy; Humans; Immunosuppressive Agents; Kidney Transplantation; Laryngeal Neoplasms; Male; Middle Aged; Radiation-Sensitizing Agents; Sirolimus; TOR Serine-Threonine Kinases

An estimated 34,000 cases of squamous cell carcinomas of the head and neck (HNSCC) will be diagnosed in 2007 with 7500 estimated deaths. Radiation is commonly used to treat these patients. Preclinical studies have suggested that sirolimus may be an effective radiosensitizer in HNSCC.. The present case report describes a patient, status post liver transplant, who was switched to sirolimus for immunosupression. The patient subsequently underwent radiation therapy for a T2N0M0 SCC of the larynx.. The patient had an unusually early response to radiation, with a clinical complete response after 7 fractions of radiation. However, the patients also had toxicity earlier than expected and required a break from radiation after 11 fractions.. To the authors' knowledge, this is the first observation to suggest that sirolimus is an effective radiosensitizer in patients with HNSCC. We hope that our results will create interest in future clinical studies.

Topics: Carcinoma, Squamous Cell; Dose Fractionation, Radiation; Humans; Immunosuppressive Agents; Laryngeal Neoplasms; Liver Transplantation; Male; Middle Aged; Radiation-Sensitizing Agents; Sirolimus

The cytotoxic effects and mechanism of action of cisplatin and the mTOR inhibitor rapamycin on Hep-2 laryngeal cancer cells were investigated. Hep-2 cells were cultured in the presence of different concentrations of rapamycin, cisplatin, or the two combined. Inhibition of cell growth, apoptosis, and AKT, mTOR, S6K, and ERCC1 protein levels were assessed. All combinations of rapamycin and cisplatin resulted in synergistic inhibition of cell growth (as indicated by q values determined using Jin's formula > 1.15). Rapamycin inhibited Hep-2 cell growth, induced G1 arrest, and when combined with cisplatin, enhanced apoptosis. p-mTOR and S6K expressions were significantly downregulated by rapamycin. ERCC1 expression was significantly upregulated with cisplatin treatment. Combined cisplatin and rapamycin treatment resulted in significant downregulated p-mTOR and S6K expression, but no change in ERCC1 expression. Rapamycin and cisplatin act in a synergistic manner, increasing the cytotoxic effect on Hep-2 cells. Rapamycin may facilitate increased Hep-2 cell apoptosis with cisplatin via inhibiting downstream expression of proteins in the AKT-mTOR signaling pathway.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; DNA-Binding Proteins; Drug Synergism; Endonucleases; Humans; Laryngeal Neoplasms; Protein Kinases; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases

Traditional immunosuppressive regimens make laryngeal transplantation in cancer patients prohibitive because of the increased risk of recurrence. Everolimus, a recently developed immunosuppressant, has demonstrated significant antitumor properties. The purpose of this study was to examine the effects of everolimus alone and in combination with other immunosuppressants on tumor growth in a combined laryngeal transplantation and tumor model.. Animal, prospective, randomized, controlled, and blinded.. One million squamous cell carcinoma cells (SCC-158) were injected intravenously into a total of 40 rats 1 day before laryngeal transplantation. Rats were divided into four groups differing by immunosuppressive regimens. Lung surface metastases were counted 21 days after inoculation, and numerical transplantation rejection scores were recorded. A separate experiment for comparison was performed with no transplant on 24 rats, but with the same immunosuppressive treatment groups.. The median number of lung surface metastases were: a) control (i.e., no immunosuppression): 85; b) everolimus 1.0 mg/kg: 25; c) tacrolimus 1.2 mg/kg: 1650; d) everolimus 1.0 mg/kg + tacrolimus 0.05 mg/kg: 1300. Rats receiving everolimus alone showed a statistically significant decrease in pulmonary surface metastases compared with the other groups. Transplanted rats had no difference in their outcomes when compared with non-transplanted rats.. Everolimus significantly decreases SCC-158 growth in our combined transplantation and tumor model compared with controls and other immunosuppressants.

Topics: Administration, Oral; Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Graft Survival; Immunosuppressive Agents; Laryngeal Neoplasms; Laryngectomy; Larynx; Lung Neoplasms; Male; Neoplasm Recurrence, Local; Neoplasm Transplantation; Rats; Rats, Inbred F344; Sirolimus; Tacrolimus

To evaluate the effect of combined use of rapamycin and cisplatin in the chemotherapy of Hep-2 cells in vitro.. The inhibitory effects of rapamycin and cisplatin, used alone or in combination, on the proliferation of Hep-2 cells were measured with MTT assay and median-effect plot analysis. The cell cycle changes after the treatment were analyzed using flow cytometry and Hoechst 33258 immunofluorescence staining.. The IC50 of rapamycin and cisplatin for inducing growth arrest of Hep-2 cells was 11.03 nmol/L and 8.81 micromol/L, respectively. Rapamycin alone caused cell cycle arrest of the Hep-2 cells in G1 phase. Rapamycin and cisplatin showed synergistic effects in the chemotherapy of Hep-2 cells (q > 1.15, King's Formula), causing significantly increased apoptosis ratio and growth inhibition rate of Hep-2 cells.. Combined use of rapamycin and cisplatin significantly improves the chemotherapeutic effect against Hep-2 cells.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Proliferation; Cisplatin; Drug Synergism; Humans; Laryngeal Neoplasms; Sirolimus; Tumor Cells, Cultured